Melatonin regulates mesenchymal stem cells differentiation : a review

none10Among the numerous functions of melatonin, the control of survival and differentiation of mesenchymal stem cells (MSCs) has been recently proposed. MSCs are a heterogeneous population of multipotent elements resident in tissues such as bone marrow, muscle, and adipose tissue, which are primarily involved in developmental and regeneration processes, gaining thus increasing interest for tissue repair and restoration therapeutic protocols. Receptor-dependent and receptor-independent responses to melatonin are suggested to occur in these cells. These involve antioxidant or redox-dependent functions of this indolamine as well as secondary effects resulting from autocrine and paracrine responses. Inflammatory cytokines and adipokines, proangiogenic/mitogenic stimuli, and other mediators that influence the differentiation processes may affect the survival and functional integrity of these mesenchymal precursor cells. In this scenario, melatonin seems to regulate signaling pathways that drive commitment and differentiation of MSC into osteogenic, chondrogenic, adipogenic, or myogenic lineages. Common pathways suggested to be involved as master regulators of these processes are the Wnt/b-catenin pathway, the MAPKs and the, TGF-b signaling. In this respect melatonin emerges a novel and potential modulator of MSC lineage commitment and adipogenic differentiation. These and other aspects of the physiological and pharmacological effects of melatonin as regulator of MSC are discussed in this review.openLuchetti, Francesca; Canonico, Barbara; Bartolini, Desiree; Arcangeletti, Marcella; Ciffolilli, Silvia; Murdolo, Giuseppe; Piroddi, Marta; Papa, Stefano; Reiter, Russel J.; Galli, FrancescoLuchetti, Francesca; Canonico, Barbara; Bartolini, Desiree; Arcangeletti, Marcella; Ciffolilli, Silvia; Murdolo, Giuseppe; Piroddi, Marta; Papa, Stefano; Reiter, Russel J.; Galli, Francesc

Xenograft of free or microencapsulated Sertoli cells as a potential therapy for experimental Type 2 Diabetes Mellitus

Introduction and Aim. Type 2 Diabetes Mellitus (T2DM), one of the world’s most important, common and costly diseases associated with devastating complications, is caused by insulin resistance mainly due to a chronic inflammation of the visceral adipose tissue with local and systemic increases in proinflammatory cytokines and adipokines such as tumor necrosis factor-α (TNF-α) and IL-6. Sertoli cells (SC), considered mere mechanical cell aids, have been recently revisited with respect to their functional competence showing that these cells may provide immunomodulatory and trophic factors that are able to ameliorate survival and development of different cell types and constitute an immuno-protective shield for transplantation in many diseases such as Type 1 Diabetes Mellitus. Aim of this work was to verify if the injection of free (subcutaneously) or microencapsulated (intraperitoneally) SC would reverse hyperglycaemia in db/db mice spontaneous T2DM Materials and Methods. Porcine pre-pubertal SC were isolated, according to previously established methods, after finely chopping the retrieval testicles, with double enzymatic digestion with Collagenase P and a mixed solution of trypsin and DNase I. SC enveloped in Barium alginate-based microcapsules (Ba-SCMCs) were prepared according to our method, by a mono air-jet device system. Free SC and Ba-SCMCs were examined as far as: (a) SC morphology by light microscopy; (b) SC viability, by fluorescence microscopy after staining with ethidium bromide and fluorescein diacetate; (c) SC in vitro function (α-aromatase activity and IGF-I secretion); (d) reversal of T2DM in spontaneous diabetes db/db mice, were concerned. Results. Ba-SCMCs showed excellent features in terms of size, morphology, sphericity and coalescence. SC viability, both in free and microencapsulated SC, was very high (over 90%). Very good α-aromatase activity and IGF-I secretion were associated with the examined SC preparations. Both subcutaneous free SC injection and intraperitoneal transplantation of Ba-SCMCs demonstrated a significant reduction, in 60% of the treated mice, of HbA1c (6.6 % vs 8.8 %) with a normalization of intraperitoneal glucose tolerance test. Conclusions. SC may be enveloped in Ba-SCMCs with no loss of their functional properties and morphology. Xenograft of SC, both free and enveloped in barium alginate microcapsules, induced an important reduction of HbA1c blood levels with a normalization of glucose tolerance test (IPGTT). This result might open new perspectives for the future therapy of human T2DM

Inflammatory Adipokines, High Molecular Weight Adiponectin, and Insulin Resistance: A Population-Based Survey in Prepubertal Schoolchildren

BackgroundThe aim of this study was to investigate sex differences and associations of high molecular weight (HMW) adiponectin, leptin and proinflammatory adipokines, individually or in combinations, with adiposity and insulin resistance (IR) measures in prepubertal childhood.MethodologyWe studied 305 prepubertal children (boys/girls: 144/161; Tanner stage 1; age: 5-13 yr), included in a cohort of 44,231 adolescents who participated in an extensive Italian school-based survey. According to Cole's criteria, 105 individuals were lean (L; boys/girls: 59/46), 60 overweight (OW; boys/girls: 32/28) and 140 obese (OB; boys/girls: 70/70). Measurements comprised total and HMW adiponectin, leptin, as well as a panel of proinflammatory adipokines/chemokines associated with diabetes risk.Principal findingsLeptin-, and the leptin-to-HMW adiponectin ratio (L/HMW)-, increased progressively (pConclusionsIn prepubertal children, leptin emerges as a sex-independent discrimination marker of adiposity degree and as a useful, sex-associated predictor of the systemic insulin resistance

Gender-specific association of body composition with inflammatory and adipose-related markers in healthy elderly Europeans from the NU-AGE study

Objectives: The aim of this work was to examine the cross-sectional relationship between body composition (BC) markers for adipose and lean tissue and bone mass, and a wide range of specific inflammatory and adipose-related markers in healthy elderly Europeans. Methods: A whole-body dual-energy X-ray absorptiometry (DXA) scan was made in 1121 healthy (65–79 years) women and men from five European countries of the “New dietary strategies addressing the specific needs of elderly population for a healthy aging in Europe” project (NCT01754012) cohort to measure markers of adipose and lean tissue and bone mass. Pro-inflammatory (IL-6, IL-6Rα, TNF-α, TNF-R1, TNF-R2, pentraxin 3, CRP, alpha-1-acid glycoprotein, albumin) and anti-inflammatory (IL-10, TGF-β1) molecules as well as adipose-related markers such as leptin, adiponectin, ghrelin, and resistin were measured by magnetic bead-based multiplex-specific immunoassays and biochemical assays. Results: BC characteristics were different in elderly women and men, and more favorable BC markers were associated with a better adipose-related inflammatory profile, with the exception of skeletal muscle mass index. No correlation was found with the body composition markers and circulating levels of some standard pro- and anti-inflammatory markers like IL-6, pentraxin 3, IL-10, TGF-β1, TNF-α, IL-6Rα, glycoprotein 130, TNF-α-R1, and TNF-α-R2. Conclusions: The association between BC and inflammatory and adipose-related biomarkers is crucial in decoding aging and pathophysiological processes, such as sarcopenia. DXA can help in understanding how the measurement of fat and muscle is important, making the way from research to clinical practice. Key Points: • Body composition markers concordantly associated positively or negatively with adipose-related and inflammatory markers, with the exception of skeletal muscle mass index. • No correlation was found with the body composition markers and circulating levels of some standard pro- and anti-inflammatory markers like IL-6, pentraxin 3, IL-10, TGF-β1, TNF-α, IL-6Rα, gp130, TNF-α-R1, and TNF-α-R2. • Skeletal muscle mass index (SMI) shows a good correlation with inflammatory profile in age-related sarcopenia

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Lipokines and oxysterols: Novel adipose-derived lipid hormones linking adipose dysfunction and insulin resistance

The expansion of adipose tissue (AT.) is, by definition, a hallmark of obesity. However, not all increases in fat mass are associated with pathophysiological cues. Indeed, whereas a "healthy" fat mass accrual, mainly in the subcutaneous depots, preserves metabolic homeostasis, explaining the occurrence of the metabolically healthy obese phenotype, "unhealthy" AT expansion is importantly associated with insulin resistance/type 2 diabetes and the metabolic syndrome. The development of a dysfunctional adipose organ may find mechanistic explanation in a reduced ability to recruit new and functional (pre)adipocytes from undifferentiated precursor cells. Such a failure of the adipogenic process underlies the "AT expandability" paradigm. The inability of AT to expand further to store excess nutrients, rather than obesity per se, induces a diabetogenic milieu by promoting the overflow and the ectopic deposition of fatty acids in insulin-dependent organs (i.e., lipotoxicity), the secretion of various metabolically detrimental adipose-derived hormones (i.e., adipoldnes and lipokines), and the occurrence of local and systemic inflammation and oxidative stress. Hitherto, fatty acids (i.e., lipokines) and the oxidation by-products of cholesterol and polyunsaturated fatty acids, such as nonenzymatic oxysterols and reactive aldehyde species, respectively, emerge as key modulators of (pre)adipocyte signaling through Wnt/beta-catenin and MAPK pathways and potential regulators of glucose homeostasis. These and other mechanistic insights linking adipose dysfunction, oxidative stress, and impairment of glucose homeostasis are discussed in this review article, which focuses on adipose peroxidation as a potential instigator of, and a putative therapeutic target for, obesity-associated metabolic dysfunctions. (C) 2013 Elsevier Inc. All rights reserved

Data-driven CAD-CAM vs traditional total contact custom insoles: A novel quantitative-statistical framework for the evaluation of insoles offloading performance in diabetic foot.

BackgroundElevated plantar pressures represent a significant risk factor for neuropathic diabetic foot (NDF) ulceration. Foot offloading, through custom-made insoles, is essential for prevention and healing of NDF ulcerations. Objective quantitative evaluation to design custom-made insoles is not a standard method. Aims: 1) to develop a novel quantitative-statistical framework (QSF) for the evaluation and design of the insoles' offloading performance through in-shoe pressure measurement; 2) to compare the pressure-relieving efficiency of traditional shape-based total contact customised insoles (TCCI) with a novel CAD-CAM approach by the QSF.MethodsWe recruited 30 neuropathic diabetic patients in cross-sectional study design. The risk-regions of interest (R-ROIs) and their areas with in-shoe peak pressure statistically ≥200kPa were identified for each patients' foot as determined on the average of peak pressure maps ascertained per each stance phase. Repeated measures Friedman test compared R-ROIs' areas in three different walking condition: flat insole (FI); TCCI and CAD-CAM insoles.ResultsAs compared with FI (20.6±12.9 cm2), both the TCCI (7±8.7 cm2) and the CAD-CAM (5.5±7.3 cm2) approaches provided a reduction of R-ROIs mean areas (pConclusionsThe CAD-CAM strategy achieves better offloading performance than the traditional shape-only based approach. The introduced QSF provides a more rigorous method to the direct 200kPa cut-off approach outlined in the literature. It provides a statistically sound methodology to evaluate the offloading insoles design and subsequent monitoring steps. QSF allows the analysis of the whole foot's plantar surface, independently from a predetermined anatomical identification/masking. QSF can provide a detailed description about how and where custom-made insole redistributes the underfoot pressure respect to the FI. Thus, its usefulness extends to the design step, helping to guide the modifications necessary to achieve optimal offloading insole performances

Adipose Tissue Plasticity in Response to Pathophysiological Cues: A Connecting Link between Obesity and Its Associated Comorbidities

Adipose tissue (AT) is a remarkably plastic and active organ with functional pleiotropism and high remodeling capacity. Although the expansion of fat mass, by definition, represents the hallmark of obesity, the dysregulation of the adipose organ emerges as the forefront of the link between adiposity and its associated metabolic and cardiovascular complications. The dysfunctional fat displays distinct biological signatures, which include enlarged fat cells, low-grade inflammation, impaired redox homeostasis, and cellular senescence. While these events are orchestrated in a cell-type, context-dependent and temporal manner, the failure of the adipose precursor cells to form new adipocytes appears to be the main instigator of the adipose dysregulation, which, ultimately, poses a deleterious milieu either by promoting ectopic lipid overspill in non-adipose targets (i.e., lipotoxicity) or by inducing an altered secretion of different adipose-derived hormones (i.e., adipokines and lipokines). This “adipocentric view” extends the previous “expandability hypothesis”, which implies a reduced plasticity of the adipose organ at the nexus between unhealthy fat expansion and the development of obesity-associated comorbidities. In this review, we will briefly summarize the potential mechanisms by which adaptive changes to variations of energy balance may impair adipose plasticity and promote fat organ dysfunction. We will also highlight the conundrum with the perturbation of the adipose microenvironment and the development of cardio-metabolic complications by focusing on adipose lipoxidation, inflammation and cellular senescence as a novel triad orchestrating the conspiracy to adipose dysfunction. Finally, we discuss the scientific rationale for proposing adipose organ plasticity as a target to curb/prevent adiposity-linked cardio-metabolic complications